The central objective of this proposal is an improved understanding of the macromolecular pathology of age-related neuronal attrition in the human brain. We seek to understand the role of the neuronal fibrous proteins, in particular, and other structural proteins in the normal age-related abiotrophy of neurons and in the pathogenesis of presenile and senile dimentia of the Alzheimer type. We will continue and expand our on-going analysis of neuronal protein abnormalities in Alzheimer's disease (AD), in comparison to tissue from age-matched normals, from Down's syndrome, and from the non-fibrillary dementia, Huntington's disease (HD). Enriched neuronal fractions and cortical homogenates will be prepared from these sources and their proteins characterized by 1- and 2-dimensional gel fractionation. We have recently identified a marked, selective augmentation of a 20,000 MW protein in AD cortical homogenates and perikaryl fractions enriched in neurons bearing paired helical filaments (PHF). We have just completed studies that definitively identify the augmented 20K protein as an increase of myelin basic protein of inttracortical origin in Alzheimer's disease. We have also found a marked increased of a 49,000 MW Protein in HD striataal homogenates. Further search for other augmented, diminished or structurally altered proteins will be made. These proteins will then be characterized by isoelectric focusing, subcellular fractionation studies, 1- and 2-D mapping, immunoelectrophoresis, immunodiffusion, etc. Immunohistological localization of altered proteins (including MBP) will be carried out in affected tissue and isolated neurons at the light and EM levels. A new technique, immunoaffinity electron microscopy, will be applied to human brain tissue to further establish the specific organelle associations of identified altered polypeptides. The pathogenic relationship, if any, between (a) perikaryal filamentous lesions, (b) axonal transport of NF proteins, and (c) the activity and transport of choline acetyltransferase in the axons of these perikarya will be studied in an experimental model of neurofibrillary disease, i.e., selective intramedullary injection of aluminum in the rabbit.